Positron emission tomography (PET) and magnetic resonance imaging (MRI) are major tools of the clinical diagnostician and the basic research scientist. They offer non-destructive three-dimensional (3D) views into deep tissues. PET, through the use of radiolabeled molecular probes can sensitively assay a range of biological processes (e.g. metabolic activity, receptor density, signal transduction) with high signal-to-noise ratio (SNR) and millimeter spatial resolution. MRI is exquisitely sensitive to soft tissue differences and abnormalities with resolution as fine as 105m in small samples. Although SNR is intrinsically low in the magnetic resonance (MR) experiment, new MRI contrast agents offer the potential of monitoring specific biological processes at high resolution, albeit at a significantly lower sensitivity than PET. Given the complementary strengths of these imaging modalities it was logical to consider integrating the two. The notion of combining these two modalities in a single instrument to allow simultaneous PET & MRI data collection was considered a curiosity at beginning of our Bioengineering Research Partnership (BRP) in 2004. Now, just four years later, there are two completed small animal PET/MRI systems (one developed by this BRP, the other in collaboration with this BRP) that have been used for a significant number of proof-of-concept in vivo studies; and the first PET/MRI system for human brain imaging has recently been developed by industry. Although PET/MRI has now become a hot topic in imaging, performance of the systems leaves much to desired and the quantitative potential of this technology for biological research has not yet been realized. The goal of this renewal is to develop a very high performance integrated 5PET/5MRI system, in which the performance of the 5PET component matches or exceeds that of commercially available standalone 5PET systems without significantly affecting the performance of the 5MR system. PET and MR data acquisition will be synchronized with each other and with physiologic monitoring triggers from subjects, thus providing the highest quality simultaneous in vivo 5PET/5MRI imaging. Real-time image reconstruction and alignment tools will provide melded PET/MR images while the experiment is in progress with data being archived and filed in an online database for intuitive and facile future access. This informatics infrastructure will provide straightforward exchange of information between collaborators and with the scientific community. In conjunction with hardware developments, we will develop techniques for highly quantitative PET/MRI studies, continue to design advanced novel dual-modality imaging agents, and we will apply our technologies, tools, and methods to assess important biological questions in animal models of human disease. The work in this BRP will continue to lay the scientific foundation for the broader application of PET/MRI technology in basic research and in the clinic.